The goal of our research is to gain an understanding of critical neuropathogenesis events and their time course after infection with HIV. We achieved important gains during our initial two years of work by developing and implementing advances in MRS, as well as applying well established techniques of neuropathology and virology, to investigate a macaque model of SIV. Through this cross-sectional approach, we showed that a significant, but reversible decrease in NAA occurs within days of SIV infection, while a large, irreversible loss of NAA is evident two years thereafter. We also found evidence of synaptodendritic injury in the SIV infected macaque, along with indications that loss of NAA is related to decreases in brain synaptophysin and calbindin. Perhaps our most provocative result was that loss of NAA may be cumulative and progress over time, with or without encephalitis. Finally, we discovered that chronic SIV infection may incite severe, heterogeneous astrocytosis, primarily affecting deep gray structures and cerebellum. Our results support the existence of indirect mechanisms of neuronal injury after HIV infection. Based on these results, our new hypotheses are that: a) SIV results in cumulative neuronal injury throughout the duration of infection; b) Loss of NAA is directly related to synaptodendritic injury sustained early in the course of SIV infection, and to the neuronal loss observed later; c) Brain injury is heterogeneous with respect to location; and d) the metabolic and pathologic abnormalities we observe in the SIV macaque model are directly related to the presence of SIV infection in the brain. To test our hypotheses, we will undertake the following research efforts: Specific Aim 1. MR spectroscopic examinations of the regional distribution, pattern and extent of changes in NAA and other metabolites in the SIV infected macaque will be performed throughout different stages of SIV infection; Specific Aim 2. Cellular pathology underlying metabolic alterations observed in the SIV brain will be identified through quantitative studies of neuronal content, synaptic and dendritic density, and astrocytosis; and Specific Aim 3. The relationship of viral infection in the brain to metabolic and pathological abnormalities subsequently observed will be determined.